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Biomedical subjects

K Squires

Publications and source records attributed to K Squires.

18 recordsLinked to original sources
PubMed1999

Constant mean viral copy number per infected cell in tissues regardless of high, low, or undetectable plasma HIV RNA.

Quantitative analysis of the relationship between virus expression and disease outcome has been critical for understanding HIV-1 pathogenesis. Yet the amount of viral RNA contained within an HIV-expressing cell and the relationship between the number of virus-producing cells and plasma virus load has not been established or reflected in models of viral dynamics. We report here a novel strategy for the coordinated analysis of virus expression in lymph node specimens. The results obtained for patients with a broad range of plasma viral loads before and after antiretroviral therapy reveal a constant mean viral (v)RNA copy number (3.6 log10 copies) per infected cell, regardless of plasma virus load or treatment status. In addition, there was a significant but nonlinear direct correlation between the frequency of vRNA+ lymph node cells and plasma vRNA. As predicted from this relationship, residual cells expressing this same mean copy number are detectable (frequency <2/10(6) cells) in tissues of treated patients who have plasma vRNA levels below the current detectable threshold (<50 copies/ml). These data suggest that fully replication-active cells are responsible for sustaining viremia after initiation of potent antiretroviral therapy and that plasma virus titers correlate, albeit in a nonlinear fashion, with the number of virus-expressing cells in lymphoid tissue.

Antiviral Agents↗
PubMed1999

Initial increase in blood CD4(+) lymphocytes after HIV antiretroviral therapy reflects redistribution from lymphoid tissues.

Previous studies proposed a dynamic, steady-state relationship between HIV-mediated cell killing and T-cell proliferation, whereby highly active antiretroviral therapy (HAART) blocks viral replication and tips the balance toward CD4(+) cell repopulation. In this report, we have analyzed blood and lymph node tissues obtained concurrently from HIV-infected patients before and after initiation of HAART. Activated T cells were significantly more frequent in lymph node tissue compared with blood at both time points. Ten weeks after HAART, the absolute number of lymphocytes per excised lymph node decreased, whereas the number of lymphocytes in the blood tended to increase. The relative proportions of lymphoid subsets were not significantly changed in tissue or blood by HAART. The expression levels of mRNA for several proinflammatory cytokines (IFN-gamma, IL-1beta, IL-6, and macrophage inflammatory protein-1alpha) were lower after HAART. After therapy, the expression of VCAM-1 and ICAM-1 -- adhesion molecules known to mediate lymphocyte sequestration in lymphoid tissue -- was also dramatically reduced. These data provide evidence suggesting that initial increases in blood CD4(+) cell counts on HAART are due to redistribution and that this redistribution is mediated by resolution of the immune activation that had sequestered T cells within lymphoid tissues.

Adult↗
PubMed1999

A randomized, controlled trial of indinavir, zidovudine, and lamivudine in adults with advanced human immunodeficiency virus type 1 infection and prior antiretroviral therapy.

A randomized, double-blind, multicenter study of indinavir, zidovudine, and lamivudine was conducted in 320 adults with human immunodeficiency virus type 1 (HIV-1) infection, </=50 CD4 cells/mm3, and extensive prior zidovudine therapy. Patients received indinavir, 800 mg every 8 h; zidovudine, 200 mg every 8 h, and lamivudine, 150 mg twice daily; or all 3 drugs for 24 weeks. In an intention-to-treat analysis, proportions of patients with HIV-1 RNA <500 and <50 copies/mL, respectively, at week 24 were 56% and 45% in the indinavir-zidovudine-lamivudine group, 3% and 2% in the indinavir group, and 0% in the zidovudine-lamivudine group. Observed mean CD4 cell increases were 95, 78, and 6 cells/mm3 in the three-, one-, and two-drug arms, respectively. Regimens were generally well tolerated. Patients with advanced HIV-1 infection benefit from triple therapy with indinavir, zidovudine, and lamivudine, although the proportion with optimal response appeared to be lower in patients with low CD4 cell counts.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Itraconazole maintenance treatment for histoplasmosis in AIDS: a prospective, multicenter trial.

PURPOSE: To study the efficacy and safety of maintenance treatment with itraconazole for disseminated histoplasmosis in patients with AIDS. PATIENTS AND METHODS: This was a prospective, multicenter, open-label study conducted at university-based hospitals participating in the AIDS Clinical Trial Group (ACTG). Forty-six AIDS patients with mild to moderate disseminated histoplasmosis who had successfully completed 12 weeks of induction treatment with itraconazole were treated with itraconazole, 200 mg once daily (42 patients) or 400 mg once daily (4 patients). Patients were followed at monthly intervals with clinical and laboratory assessment for relapse or toxicity. Primary outcome measures were relapse of histoplasmosis and survival. Secondary outcome measures included drug-limiting toxicity and changes in serum and urine Histoplasma polysaccharide antigen (HPA) levels. RESULTS: Two patients relapsed during a median follow-up period of 87 weeks. The 1-year relapse-free rate was estimated to be 95.3% (95% CI, 85.3%-99.7%). One relapse may have been related to poor adherence to treatment and the second to concurrent administration of rifampin. From the start of maintenance treatment, the estimated 1-year survival rate was 73.0% (95% CI, 67.5%-77.9%). Five patients discontinued treatment because of suspected drug toxicity, three of whom had possible or probable hepatotoxicity. Median serum and urine HPA levels declined significantly during treatment. The only patient in whom antigen levels rose >2 U developed clinical relapse 1 week later; antigen levels were unavailable in the other relapsing patient. CONCLUSIONS: Itraconazole, 200 mg daily, is effective in preventing relapse of disseminated histoplasmosis in patients with AIDS. It is generally well tolerated, but clinicians should be alert for drug interactions and possible hepatotoxicity.

AIDS-Related Opportunistic Infections↗
PubMed1997

Phase I dose-escalation pharmacokinetics of AZT-P-ddI (IVX-E-59) in patients with human immunodeficiency virus.

3'-Azido-3'-deoxythymidilyl-(5',5')-2',3'-dideoxy-5'-inosinic acid (AZT-P-ddI, IVX-E-59, Scriptene) is a heterodimer composed of one molecule of 3'-azido-3'-deoxythymidine (zidovudine or AZT) and one molecule of 2',3'-dideoxyinosine (didanosine or ddI) linked through their 5' positions by a phosphate bond. AZT-P-ddI exhibits enhanced antiviral activity and selectivity in vitro compared with AZT and ddI alone. The pharmacokinetics of AZT-P-ddI were studied in 12 patients with human immunodeficiency virus (HIV) who had CD4+ cell counts higher than 200 cells/mm3. Isotopic preparations of (14C)-AZT-P-(3H)-ddI were administered intravenously (50 mg and 100 mg) to eight patients; 1 month later these patients were crossed over to oral administration (100 mg and 200 mg). A second group of patients (n = 4) received only a 450-mg oral dose of AZT-P-ddI. Plasma levels of unchanged AZT-P-ddI after intravenous infusion declined rapidly and were undetectable 0.75 hours after the end of infusion, whereas the parent compound was not detected after oral administration, indicative of a very rapid metabolism. The parent entity was enzymatically cleaved in vivo yielding the two constituent drugs AZT and ddI, which were subsequently subjected to their respective pharmacokinetic and metabolic processes. The beta-glucuronide derivative of AZT (GAZT) represented the major metabolite of AZT, but there were no detectable levels of the toxic metabolite 3'-amino-3'-deoxythymidine (AMT). A major and previously unrecognized in vivo metabolite of ddI, referred as ddI-M, was detected in plasma and urine. Analysis by high-field proton nuclear magnetic resonance and mass spectrometry led to the identification of ddI-M as being R(-)-dihydro-5-(hydroxymethyl)-2(3H)-furanone. The formation of AZT and ddI metabolites was increased after oral administration of AZT-P-ddI compared with the intravenous infusion, with an area under the concentration-time curve (AUC) ratio of metabolite to AZT and metabolite to ddI being 7.7 and 5.7 (oral) and 3.8 and 1.1 (intravenous), respectively. The newly identified ddI-M exhibited sustained plasma levels for extended time periods with an apparent elimination half-life (t1/2) of approximately 10 hours after oral administration of AZT-P-ddI. Recovery of radioactivity associated with 3H and 14C in urine was essentially complete within 48 hours after oral and intravenous administration of AZT-P-ddI. The oral bioavailability of AZT (64.7-67.3%) and ddI (33.6-42.9%) and the other pharmacokinetic parameters were consistent with previous data reported with each nucleoside analog alone or in combination therapy.

Administration, Oral↗
PubMed1997

Treatment of histoplasmosis with fluconazole in patients with acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Acquired Immunodeficiency Syndrome Clinical Trials Group and Mycoses Study Group.

PURPOSE: This study assesses the efficacy and safety of fluconazole therapy in patients with acquired immunodeficiency syndrome (AIDS) and mild to moderately severe manifestations of disseminated histoplasmosis. PATIENTS AND METHODS: This was a multicenter, open-label, nonrandomized prospective trial. All patients had AIDS and disseminated histoplasmosis. Patients were treated with 1,200 mg of fluconazole given by mouth once on the first day, then 600 mg once daily for 8 weeks, and those patients who improved clinically were then assigned fluconazole maintenance therapy 200 mg once daily for at least 1 year. Interim analysis revealed a high failure rate (10 of 20, 50%), causing revision of the protocol to increase the fluconazole dose to 1,600 mg given once on the first day, then 800 mg once daily, and the duration to 12 weeks for induction therapy and then 400 mg daily for 1 year for maintenance therapy. MEASUREMENTS AND MAIN RESULTS: Thirty-six of 49 patients (74%; 95% confidence interval [CI]: 59% to 85%) with mild to moderately severe clinical manifestations who entered into the revised study responded to 800 mg of fluconazole daily for 12 weeks as induction therapy. Of the seven patients who failed induction therapy because of progression of histoplasmosis, one died of the infection. Of 36 patients who entered into the maintenance phase of the study receiving 400 mg of fluconazole daily for 1 year, 11 (30.5%) relapsed, including one who died (2.8%). Two of the 49 patients (4.1%) were removed because of grade 4 adverse events, alkaline phosphatase elevation for one and aspartate aminotransferase elevation in the other. The relapse-free rate at 1 year was 53% (95% CI: 32% to 89%), prompting closure of the study. CONCLUSIONS: Fluconazole 800 mg daily is a safe and moderately effective induction therapy for mild or moderately severe disseminated histoplasmosis in patients with AIDS. On the basis of historic comparison, fluconazole 400 mg daily is less effective than itraconazole 200 to 400 mg daily or amphotericin B 50 mg given weekly as maintenance therapy to prevent relapse.

AIDS-Related Opportunistic Infections↗
PubMed1997

Pharmacokinetics of saquinavir, zidovudine, and zalcitabine in combination therapy.

We investigated the pharmacokinetics of zidovudine, zalcitabine, and saquinavir in AIDS Clinical Trial Group protocol 229. Patients received either saquinavir, zalcitabine, or a combination of both, together with zidovudine three times a day. Approximately 100 patients were enrolled in each treatment arm, and intensive pharmacokinetic studies were performed on about 25 patients per arm at weeks 1 and 12. We estimated the pharmacokinetic parameters of all three drugs by using parametric and nonparametric methods. The mean values of the pharmacokinetic parameters of zidovudine (clearance [CL]/bioavailability [F], 168 liters/h; volume of distribution [V]/F, 185 liters; half-life, 0.76 h) and zalcitabine (CL/F, 25 liters/h; V/F, 92.2 liters; half-life, 2.7 h) were similar to those reported previously. For saquinavir, the mean pharmacokinetic parameter estimates using parametric methods were as follows: maximum concentration of drug in serum [Cmax], 70.8 ng/ml; time to Cmax, 3.11 h; area under the curve, 809 ng x h/ml; CL/F, 989 liters/h; V/F, 1,503 liters; half-life, 1.38 h. For all three drugs, clearance decreased with age. Weight did not influence the clearance of zidovudine, but the clearance of zalcitabine and saquinavir increased with weight. There were no differences in pharmacokinetic parameters between study weeks and arms, suggesting that there is no change in kinetics with chronic administration and that there are no significant pharmacokinetic interactions among these three drugs.

Adult↗
PubMed1995

Dramatic decrease in tuberculin skin test conversion rate among employees at a hospital in New York City.

BACKGROUND: The Centers for Disease Control and Prevention recently issued updated guidelines for preventing the transmission of tuberculosis in health care facilities. Many recommendations, including the use of high-efficiency particulate air filter respirators, are expensive to implement and of unproven efficacy. We therefore reviewed the tuberculin skin test conversion rate among our employees from 1991 to 1993, before introduction of high-efficiency particulate air filter respirators. During this period, several other improvements in tuberculosis control were implemented. METHODS: Employee tuberculin test conversion rates were reviewed by 6-month interval from 1991 to 1993. RESULTS: Throughout the study period, several tuberculosis control measures were implemented, including early isolation of patients with suspected cases of tuberculosis in rooms with negative-pressure ventilation, placement of germicidal UV light fixtures into patient rooms and common areas, and use of Technol shields (Technol, Inc., Fort Worth, Texas) (1991), particulate respirators (1992), and dust-mist-fume respirators (1993). With these improvements, the conversion rate among employees fell from 20.7% in the first 6 months of 1991 to 5.8% in the latter half of 1993. CONCLUSIONS: The rate of skin test conversion among our employees decreased before introduction of high-efficiency particulate air filter respirators. This suggests that nosocomial spread of tuberculosis can be decreased by means of previously established, less costly methods.

Cross Infection↗
PubMed1995

Pharmacokinetic, safety, and antiviral profiles of oral ganciclovir in persons infected with human immunodeficiency virus: a phase I/II study. AIDS Clinical Trials Group, and Cytomegalovirus Cooperative Study Group.

A phase I/II study evaluated the pharmacokinetics, tolerability, and antiviral activity of oral ganciclovir in persons infected with human immunodeficiency virus (HIV). Oral bioavailability ranged from 2.6% to 7.3%. The mean maximum serum concentration achieved at 1000 mg every 8 h was 1.11 micrograms/mL, and mean trough level was 0.54 microgram/mL. The time to maximum serum drug concentration was 1.0-2.9 h, with a serum half-life of 3.0-7.3 h, suggesting prolonged oral absorption. Serious adverse events were uncommon. Decreased cytomegalovirus (CMV) shedding was observed from all sites. The median days (by dosage) to retinitis progression assessed by retinal examination after initiation of oral ganciclovir were 62 (1000 mg every 8 h), 148 (500 mg every 3 h), 75 (750 mg every 3 h), 148 (1000 mg every 3 h), and 139 (2000 mg every 8 h). Thus, oral ganciclovir has pharmacokinetic, toxicity, and antiviral profiles that may prove beneficial for both maintenance therapy of CMV retinitis and prevention of CMV disease in HIV-infected persons.

Administration, Oral↗
PubMed1995

Population pharmacokinetics of stavudine (d4T) in patients with AIDS or advanced AIDS-related complex.

The population pharmacokinetics and bioavailability of oral stavudine (d4T; 2',3'-dideoxy-3'-deoxythymidine) was determined in 81 patients with AIDS or AIDS-related complex (ARC) enrolled in phase I and phase I/II dose-ranging trials. Each patient underwent inpatient pharmacokinetic studies following administration of the first oral stavudine dose; 59 patients were restudied after chronic therapy for an average of 19 days. Thirty-three of these patients also received a single intravenous stavudine dose prior to starting an oral regimen. A two-compartment model with first-order absorption and elimination was used as the structural pharmacokinetic model. A basic model provided the following population parameter estimates (interpatient variability expressed in parentheses as percent coefficient of variation): clearance/bioavailability = 30.9 (24.5%) liters/h; volume of distribution/bioavailability = 8.42 (not modeled) liters; volume of distribution at steady state/bioavailability = 68.9 (105%) liters; intercompartmental clearance/bioavailability = 12.4 (26%) liters/h; and first-order absorption rate constant = 1.32 (78.9%) liters/h. In the subset of 33 patients receiving both intravenous and oral doses, the bioavailability of stavudine was estimated to be 99.1% (18.5%). Total body weight, stage of disease (AIDS versus ARC), and an oral stavudine dose of > or = 200 mg were found to have a statistically significant but a clinically marginal effect on the estimate of the oral clearance of stavudine. This analysis shows the high degree of bioavailability of stavudine in patients with AIDS and ARC and the relatively low degree of interpatient variability in oral drug clearance compared with those of other nucleosides. Population pharmacokinetic analysis is a useful tool for assessing the combined effects of several patient variables on the pharmacokinetic properties of drugs in human immunodeficiency virus-infected patients.

AIDS-Related Complex↗
PubMed1994

Defining care.

Explore the source record for details and available documents.

Female↗
PubMed1993

Prevention of relapse of histoplasmosis with itraconazole in patients with the acquired immunodeficiency syndrome.

OBJECTIVE: To assess the efficacy and safety of itraconazole in preventing relapse of histoplasmosis after induction therapy with amphotericin B in patients with the acquired immunodeficiency syndrome (AIDS) and disseminated histoplasmosis. DESIGN: A prospective, multicenter, open-label clinical trial, with follow-up for at least 52 weeks. SETTING: Tertiary care hospitals participating in a clinical investigation sponsored by the National Institutes of Allergy and Infectious Diseases (AIDS Clinical Trial Group and Mycoses Study Group). PATIENTS: Forty-two patients with AIDS who had successfully completed induction therapy for disseminated histoplasmosis amphotericin B, at least 15 mg/kg body weight given over 4 to 12 weeks. INTERVENTIONS: Itraconazole, 200 mg given orally twice daily. MAIN OUTCOME MEASURES: Response to therapy, specifically prevention of histoplasmosis relapse, was the main outcome measure. Secondary end points were survival and the effect of therapy on Histoplasma capsulatum variety capsulatum antigen levels in urine and serum. Plasma itraconazole concentrations were measured to document drug absorption and compliance with therapy. RESULTS: The median follow-up was 109 weeks, and median survival was 98 weeks. Two relapses occurred (5%; 95% CI, 0.5% to 16%), one in a patient withdrawn from the study 18 weeks earlier and one in a patient who did not comply with the study therapy. Patients with elevated antigen levels at study entry showed clearance of antigen from urine and serum; urine specimens became negative in 43% of patients (CI, 26% to 59%), and serum specimens became negative in 75% of patients (CI, 56% to 94%). Only one patient discontinued treatment because of itraconazole toxicity (hypokalemia). CONCLUSIONS: Itraconazole, 200 mg twice daily, is safe and effective in preventing relapse of disseminated histoplasmosis in patients with AIDS. Antigen clearance from blood and urine correlates with clinical efficacy.

AIDS-Related Opportunistic Infections↗
PubMed1992

Fluconazole compared with ketoconazole for the treatment of Candida esophagitis in AIDS. A randomized trial.

OBJECTIVE: To determine the clinical and endoscopic response of candida esophagitis to antifungal therapy and to compare the two oral antifungal agents, fluconazole and ketoconazole. DESIGN: Multicenter, randomized, double-blind trial. SETTING: Fifteen U.S. centers including university, private practice, and county hospital settings. PATIENTS: A total of 169 patients with the acquired immunodeficiency syndrome (AIDS); odynophagia, dysphagia, or retrosternal pain; white esophageal plaques at endoscopy; and pseudohyphae on esophageal brushings or biopsies. INTERVENTION: Patients were randomly assigned to fluconazole (100 mg/d) or ketoconazole (200 mg/d). Doses were doubled at week 1 or 2 if no symptomatic improvement had occurred during the preceding week. Therapy was continued for 2 weeks after resolution of symptoms or for a maximum of 8 weeks. MEASUREMENTS: Patients were clinically evaluated weekly, and laboratory tests were done every 2 weeks. Endoscopy was repeated within 5 days after the end of therapy. RESULTS: A total of 143 patients were clinically evaluable (assessed within 7 days after therapy), and 129 patients were endoscopically evaluable (endoscopy repeated after therapy). Endoscopic cure occurred in 91% of patients treated with fluconazole and in 52% of those given ketoconazole for a difference of 39% (95% Cl, 24% to 52%; P less than 0.001). Esophageal symptoms resolved in 85% of fluconazole-treated patients and in 65% of ketoconazole-treated patients for a difference of 20% (Cl, 6% to 34%; P = 0.006). Intention-to-treat analyses also yielded statistically significant differences for the comparisons listed above. Side effects were minimal and comparable in the two groups; only one patient in each group had therapy discontinued for adverse effects that were possibly related to the study medications. CONCLUSIONS: Fluconazole is associated with significantly greater rates of endoscopic and clinical cure than ketoconazole in patients with AIDS and candida esophagitis. Both drugs appear to be safe and well tolerated.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Widespread intradermal accumulation of mononuclear leukocytes in lepromatous leprosy patients treated systemically with recombinant interferon gamma.

Intradermal administration of recombinant interferon gamma (rIFN-gamma) to lepromatous leprosy patients has converted the local histology toward a tuberculoid pattern. However, such changes have been confined to the site of injection. In contrast, in the present study, marked, intradermal accumulation of CD3+, CD4+, CD8+, and CD1a+ T cells and Leu-M5+ mononuclear phagocytes was induced at a distance from the sites of administration, in a dose-dependent manner, by 10 daily intramuscular injections of 10-30 micrograms rIFN-gamma/m2. Mononuclear cell infiltration began within 3 d of onset of rIFN-gamma therapy and persisted at least 8 wk. Intramuscular administration of rIFN-gamma to lepromatous patients receiving concurrent chemotherapy can safely induce widespread histologic features of an upgrading reaction.

Adult↗
PubMed1982

Distribution of auditory brainstem potentials over the scalp and nasopharynx in humans.

Auditory brainstem potentials were recorded from various scalp and nasopharyngeal sites referenced both to a noncephalic site and to certain scalp locations in normal humans. The distribution of amplitudes and latencies of the components were defined. There were significant amplitude, polarity, and latency asymmetries over the scalp in both referential and differential recordings. The data indicated that several of the ABR components have generator sources that are lateralized and move through the brainstem in particular orientations.

Adult↗
PubMedDate not supplied

Multidisciplinary approach used to improve infant care.

Many of the implemented changes have required the rewriting of standards of care and policies, as well as the education of staff. Staff education was addressed through a variety of approaches, including one-hour inservice training sessions and eight-hour courses. In the final analysis, the multidisciplinary QA committee has had a significant impact on improving the processes involved in caring for infants with RDS. Because of this success, committee members have acknowledged that all aspects of patient care may be examined and changes implemented when caregivers keep an open mind and are willing to change the way "things have always been done." This commitment to examine all aspects of care and to implement change has been, for Presbyterian Hospital, the key to genuine quality improvement. As a result of these and other efforts, Presbyterian Hospital has improved the care given to all of its patients. In March 1992, the hospital received accreditation with commendation.

Ancillary Services, Hospital↗